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At least 631 records · Page 35Linked to original sources
PubMed2002

Syngeneic stem cell transplant for spent-phase polycythaemia vera: eradication of myelofibrosis and restoration of normal haematopoiesis.

We report a patient with spent-phase polycythaemia vera (S-PV) and massive splenomegaly who failed to engraft after a syngeneic granulocyte colony-stimulating factor-primed peripheral blood stem cell transplant (SCT), but later engrafted after splenectomy. Bone marrow (BM) showed resolution of myelofibrosis (MF) and absent endogenous erythroid colonies. This case demonstrated that (1) normal haematopoiesis can be restored after syngeneic SCT despite extensive MF, and (2) fibrosis can regress following a total body irradiation-containing regimen and syngeneic SCT. As a graft-versus-BM stroma effect is non-existent in syngeneic transplants, there may be a role for autologous SCT to obliterate MF in S-PV.

Combined Modality Therapy↗
PubMed2002

Thalidomide treatment in myelofibrosis with myeloid metaplasia.

Myelofibrosis with myeloid metaplasia (MMM) is uniquely characterized by macroscopic bone marrow stromal changes that are believed to be both reactive and cytokine mediated. Furthermore, a prognostically detrimental increase in bone marrow angiogenesis has recently been demonstrated. These observations suggest a potential therapeutic role for agents that are inhibitory to angiogenesis as well as cytokines that are pathogenetically implicated in MMM. In a prospective study of 15 patients with MMM, thalidomide treatment, starting at a dose of 200 mg/d, resulted in increased platelet counts (12 of 15 patients), increased haemoglobin level (3 of 15), a modest decrease in spleen size (3 of 12), increased bone marrow megakaryopoiesis (5 of 9) and decreased bone marrow angiogenesis (2 of 9). Undesirable haematological effects included pericardial extramedullary haematopoiesis in one patient, marked leucocytosis in two patients and extreme thrombocytosis in three patients. The thrombocytosis occurred in both patients with post-thrombocythaemic myeloid metaplasia (PTMM) and was also associated with higher baseline levels of circulating CD34+ cells. Previously described toxicities of thalidomide were seen in the majority of patients and dose escalation to 400 mg/d was permitted in only two patients. In contrast, toxicity-related dose reductions to 50 mg/d did not appear to lessen drug efficacy. We conclude that thalidomide has both beneficial and potentially adverse biological activity in MMM. A lower dose of the drug might be more tolerable without compromising therapeutic value. Patients with PTMM and/or markedly increased circulating CD34+ cell counts might be susceptible to thalidomide-induced thrombocytosis.

Adult↗
PubMed2002

Myelofibrosis with myeloid metaplasia following essential thrombocythaemia: actuarial probability, presenting characteristics and evolution in a series of 195 patients.

Myelofibrotic transformation is a known complication of essential thrombocythaemia (ET), but information on its incidence, presenting features and evolution is scarce. In a series of 195 patients with ET followed for a median of 7.2 years (range: 1.9-24), evolution into myelofibrosis with myeloid metaplasia (MMM) occurred in 13 cases, a median of 8 years (range: 3.6-20.2) from diagnosis. The actuarial probability of this complication was 2.7% (95% CI: 2.4-2.9) at 5 years, 8.3% (95% CI: 7.8-8.9) at 10 years, and 15.3% (95% CI: 6.1-24.5) at 15 years. Four patients had not been treated before developing MMM. The main features indicating this condition were the appearance of immature myeloid precursors in the peripheral blood, a decrease in the Hb value not related to treatment and increased serum lactate dehydrogenase levels, followed by a progressive decrease in the platelet count, increasing leucocytosis and progressive splenomegaly. No patient had constitutional symptoms, and none of five evaluable cases showed chromosome abnormalities in bone marrow or unstimulated blood. After a median the myelofibrotic transformation, three patients have died and four have not required treatment for MMM as yet.

Adolescent↗
PubMed2002

Low-dose, single-fraction, whole-lung radiotherapy for pulmonary hypertension associated with myelofibrosis with myeloid metaplasia.

Pulmonary hypertension (PH) can complicate myelofibrosis with myeloid metaplasia (MMM), may arise in the absence of evidence for thromboembolic disease and carries a grim prognosis. Four patients with MMM and severe symptomatic PH were treated with whole-lung external beam radiotherapy in a single fraction of 100 cGy. Within 72 h, each patient noted marked symptomatic improvement and had relief of hypoxia and reduction of oedema and/or ascites. Three of the four patients enjoyed an objective improvement in pulmonary artery systolic pressure as measured by transthoracic Doppler echocardiography. Low-dose lung radiotherapy may be a useful palliative tool for patients with MMM complicated by PH.

Aged↗
PubMed2002

Dose-reduced conditioning regimen followed by allogeneic stem cell transplantation in patients with myelofibrosis with myeloid metaplasia.

Three patients with myelofibrosis received allogeneic stem cell transplantation after a dose-reduced conditioning regimen of busulphan (8 mg/kg), fludarabine (180 mg/m2) and antithymocyte globulin (4 x 10 mg/kg). The median age at transplantation was 51 years (range 44-58). All patients engrafted with a leucocyte count > 1.0 x 10(9)/l after a median of 18 d (range 16-20). Grade II acute skin graft-versus-host disease (GvHD) occurred in one patient. One limited and one extensive chronic GvHD was observed. All patients achieved complete haematological remission. In one patient the fibrosis resolved completely 180 d post transplant. All patients are alive 126, 466 and 764 d after transplantation.

Adult↗
PubMed2003

Carboxy-terminal fragment of osteogenic growth peptide in vitro increases bone marrow cell density in idiopathic myelofibrosis.

Idiopathic myelofibrosis (IMF) is a clonal stem cell disorder characterized by reactive fibrosis of bone marrow sustained by a complex cytokine network. At present, no efficacious therapy for this disease exists. Synthetic carboxy-terminal pentapeptide of osteogenic growth factor (sOGP10-14) can increase bone marrow cellularity and the number of haematopoietic colonies; this study evaluated the activity of sOGP10-14 in IMF. Fragments of bone marrow biopsies from patients affected by IMF were cultured with or without the addition of sOGP10-14. Cellular density was evaluated by image analysis, and transforming growth factor-beta1 (TGF-beta1) concentration was immunologically assayed in the supernatant of cultured bone marrow biopsies. The proliferation rate of the megakaryoblastic M07-e cell line, cultured in the presence of either granulocyte-macrophage colony stimulating factor or thrombopoietin (TPO), and with or without sOGP10-14, was evaluated. Megakaryocyte colony forming unit (CFU-Mk) assay was performed on bone marrow samples of IMF patients with or without sOGP10-14. After 14 d, bone marrow cellularity was significantly increased in samples cultured with the pentapeptide. Moreover, sOGP10-14 induced a significant increase of TGF-beta in culture supernatants. TPO-primed proliferation of M07-e was reduced by sOGP10-14, and the pentapeptide significantly reduced CFU-Mk on IMF bone-marrow-derived cells. sOGP10-14 increased ex vivo bone marrow cellularity in IMF. This action could be related to the megakaryocyte inhibition induced by the interference of this pentapeptide with growth factor activities. These findings suggest that a deficiency of osteoblast-related factors may play a role in bone marrow failure in IMF.

Aged↗
PubMed2004

Transplant strategies for idiopathic myelofibrosis.

Idiopathic myelofibrosis (IMF) is a clonal stem cell disorder and is one of the four major myeloproliferative disorders, which include essential thrombocythemia (ET), polycythemia vera (PV), and chronic myelogenous leukemia (CML). Patients may be asymptomatic at the early stages, but later progress to marrow fibrosis, splenomegaly with pancytopenia leading to anemia, and other constitutional symptoms. Most of the care available is supportive and only palliates the constitutional symptoms. Prognosis for these patients is dependent on karyotype, hemoglobin count, and age. Stem cell transplantation is the only curative therapy, which results in eradication of the stem cell clone, with the cessation of extramedullary hematopoiesis and resolution of marrow fibrosis and its sequelae. Stem cell replacement therapy using either autologous or allogeneic stem cells has been attempted in small populations of patients with variable benefit. A nonmyeloablative approach has shown promise in a very small number of patients, but additional investigation is required for the ideal management of these patients.

Disease Management↗
PubMed2005

Myelofibrosis with myeloid metaplasia: diagnosis, prognostic factors, and staging.

Myelofibrosis with myeloid metaplasia (MMM) is an infrequent disease usually affecting elderly people. Due to the lack of a specific marker for MMM, efforts are being made to refine the diagnostic criteria. A prefibrotic form of the disease has recently been recognized and a set of diagnostic criteria proposed by the Italian Consensus Conference for the Diagnostic Criteria of MMM. Moreover, the number of circulating CD34(+) cells has recently been proven to be useful in the differential diagnosis of the disease. Median survival of patients with MMM is about 5 years, but there is wide variability. Hemoglobin level at diagnosis is the most important prognostic factor, whereas age, constitutional symptoms, low or high leukocyte counts, blood blast cells, cytogenetic abnormalities, and number of circulating CD34(+) cells are also of prognostic value. Based on some of the above factors, several prognostic systems of MMM have been proposed to identify at presentation subgroups of patients with a different risk profile. This is especially important in younger individuals, who may benefit from therapies that have curative potential but also involve a mortality risk (notably, allogeneic hemopoietic stem cell transplantation). Since no disease-oriented therapies for MMM are currently available and treatment is based on palliation and improvement of quality of life, therapy should be formulated according to the form of presentation of the disease and its prognostic implications. A staging system for MMM that meets treatment requirements and available therapeutic resources should be developed by considering parameters able to predict not only survival but also other disease outcomes, such as development of anemia, thrombocytopenia, splenomegaly, and blast transformation. Such a staging system should be derived from a large population of patients, systematically collected from diagnosis without selection bias and followed over time.

Chronic Disease↗
PubMed2005

Surgical and radiotherapeutic approaches for myelofibrosis with myeloid metaplasia.

Sequestration of circulating immature myeloid progenitors in the chronic myeloproliferative disorder myelofibrosis with myeloid metaplasia (MMM) leads to extramedullary hematopoiesis (EMH), as well as end organ enlargement and dysfunction. When medical therapy is inadequate to control symptomatic myeloproliferation, both surgical resection and/or external beam radiotherapy may provide palliative cytoreduction in specific situations. Therapeutic splenectomy may provide relief of pain, mass effect, an improvement in cytopenias, or even palliation of portal hypertension. However, the risks of perioperative and long-term complications limit the use of splenectomy in MMM to specific candidates. In addition to splenectomy, portal hypertension has been palliated by either elective esophageal variceal ligation or porto-systemic shunting (through either open or invasive radiographic means). External beam radiotherapy can provide palliative cytoreduction in afflicted organs, with the greatest benefit seen in the lungs and spine. Splenic radiation also can provide a decrease in the size of the organ but carries the risk of myelosuppression and potentially increases the risk associated with subsequent splenectomy. Hepatic and abdominal radiation may palliate hepatomegaly and/or ascites, but cytopenias are common and responses brief. Novel therapies aimed at the pathogenesis of the disorder are needed for more efficacious and targeted therapy of MMM.

Algorithms↗
PubMed2005

Hematopoietic stem cell transplantation for myelofibrosis.

Myelofibrosis with myeloid metaplasia (MMM) is a clonal disorder resulting from the proliferation of aberrant hematopoietic progenitors. Hence MMM is curable if the abnormal clone can be eradicated and replaced by normal cells from healthy donors. Myeloablative allogeneic transplantation results in high rates of durable engraftment and cure in approximately 50% of patients. Treatment-related mortality rather than disease recurrence accounts for the majority of treatment failures. Higher rates of treatment failure are associated with more advanced disease and age. More recently, nonmyeloablative (reduced-intensity) conditioning regimens have been shown to induce encouraging rates of engraftment and prolonged survival. When recommending transplantation for a particular patient, the prospect of cure should be weighed against the considerable risks of the procedure. Transplantation is typically recommended for patients under the age of 50 years with intermediate- and high-risk features, or for patients aged 50 to 60 years with an anticipated survival of less than 5 years. Finally, autologous transplantation has also been evaluated as a potential treatment approach. This procedure is unlikely to be curative, but might have a palliative role.

Chronic Disease↗
PubMed2005

Conventional and new treatment options for myelofibrosis with myeloid metaplasia.

The pathogenetic mechanisms underlying the clonal myeloproliferation and reactive marrow fibrosis that characterize myelofibrosis with myeloid metaplasia (MMM) are poorly understood. Recent advances into the pathophysiology of the disease have not yet translated into effective therapeutic options for patients. There is no standard treatment, and no therapies identified yet, besides allogeneic stem cell transplantation, that will significantly change the natural history of MMM. Treatment is therefore palliative and is geared towards alleviating symptoms of the disease and improving blood counts. Conventional therapies for anemia include androgens and corticosteroids. Cytoreductive agents such as hydroxyurea are indicated for symptomatic organomegaly and the control of leucocytosis or thrombocytosis. Several novel agents have been investigated in the recent past, and include antiangiogenic agents and signal transduction inhibitors that target the angiogenic and fibrogenic cytokines that have been implicated in the pathogenesis of the detrimental bone marrow stromal reaction. Ultimately, an improved understanding of the biological factors that cause the clonal myeloproliferation in MMM will lead to the development of effective therapeutic interventions.

Androgens↗
PubMed2003

Treatment approaches in myelofibrosis with myeloid metaplasia: the old and the new.

Myelofibrosis with myeloid metaplasia (MMM) is currently classified as a chronic myeloproliferative disorder (CMPD) and is characterized by prominent bone marrow stromal reaction including collagen fibrosis, osteosclerosis, and angiogenesis. Among the CMPD, MMM carries the worst prognosis with an overall median survival of 5 years; the clinical course is marred by profound constitutional symptoms, progressive anemia, and symptomatic splenomegaly. Causes of death include leukemic transformation, which occurs in approximately 10% of patients in the first decade of the disease. At present, allogeneic hematopoietic stem cell transplantation (HSCT) is the only treatment modality that has the potential to either cure the disease or prolong survival. Both drug therapy and autologous HSCT are currently palliative. Conventional treatment agents in MMM include androgen preparations, corticosteroids, erythropoietin (EPO), and hydroxyurea. In addition, both splenectomy and radiation therapy have defined therapeutic roles. Thalidomide is the most effective investigational agent at the present time. Optimal therapy for an individual patient requires a sound understanding of disease risk factors, as well as a full appreciation of the risk to benefit ratio for a specific treatment modality.

Angiogenesis Inhibitors↗
PubMed1999

Splenic irradiation in myelofibrosis with myeloid metaplasia: a review.

Morbidity from myeloid metaplasia and myelofibrosis arises from progressive anemia and abdominal discomfort related to massive splenomegaly, which may be associated with hypercatabolic symptoms. To date, no therapy, other than allogeneic bone marrow transplantation, has been shown to cure or to prolong the survival of these patients. Thus, current management strategies are palliative and include red cell transfusional support and androgen therapy for anemia; chemotherapeutic agents for control of thrombocytosis, leukocytosis, and hypermetabolic symptoms; and splenectomy or splenic irradiation for symptomatic splenomegaly. The major indication for splenic irradiation is left upper quadrant discomfort related to massive splenomegaly, usually in patients for whom splenectomy is contraindicated or has been declined. In most patients, it provides relief from abdominal pain and a moderate reduction in splenic size. Although responses are transient, some patients may experience prolonged relief. Splenic irradiation can result in prolonged myelosuppression in certain patients. This calls for cautious dosing, because individual sensitivity is variable and cannot be predicted. The use of splenic irradiation does not preclude subsequent splenectomy; however, the increased risk of postoperative hemorrhage should discourage consideration of splenic irradiation as an alternative or a temporizing measure before splenectomy when indicated.

Humans↗
PubMed1975

[Radiological features of the rectal manifestations of myelofibrosis(author's transl)].

In addition to the well known changes in bone structure, myelofibrosis can result in extramedullary tumour formation; in the gastr-intestinal tract, proliferation of reticulum can lead to fibrotic changes. This results in appearances similar to linitis plastica or Crohn's disease. In the discussion, the authors refer to tumours in other organs which have been described in the literature and which can be demonstrated radiologically.

Autopsy↗
PubMed1978

[Transitory myelofibrosis in a case of diaphyseal dysplasia (Camurati-Engelmann's disease) (author's transl)].

A Greek child aged 2 with diaphyseal dysplasia developed an anaemia which required transfusion. The liver, spleen and lymph nodes were enlarged, there was pancytopenia and polyclonal hypergammaglobulinaemia. Biopsy provided evidence for myelofibrosis with extramedullary erythropoiesis. He was treated with small doses of corticosteroids and during his third year there was complete regression of the disease without recurrence when treatment was stopped. Disturbances of haematopoiesis in diaphyseal dysplasia has not been reported previously. These unusual findings are of clinical interest and also affect the clinical diagnosis.

Bone Diseases, Developmental↗
PubMed2004

A patient with myelofibrosis complicated by refractory ascites and portal hypertension: to tips or not to tips? A case report with discussion of the mechanism of ascites formation.

In patients with myelofibrosis, clinically significant portal hypertension is known to be predominantly presinusoidal; however, the exact mechanisms are still controversial. The pathophysiology is particularly enigmatic in those patients without histological and angiographic evidence of significant intra- or extrahepatic obstruction to portal blood flow, respectively. Moreover, ascites formation has been reported in such cases, but in general is rare in presinusoidal portal hypertension. Here we present such a patient in which ascites developed even in the presence of unchanged serum protein levels (oncotic pressure) and was refractory to sodium restricted diet and high-dose diuretic treatment. A discussion on the parameters influencing fluid exchange and ascites formation particularly emphasizing the potential importance of the hyperdynamic circulation in this case is given. Finally, the patient was treated by implanting a transjugular intrahepatic shunt (TIPS), exerting a diuretic effect sufficient enough to avoid re-formation of ascites for several months. However, ascites re-accumulated potentially due to the appearance of ectopic peritoneal myeloid metaplasia and the patient died soon afterwards. In conclusion, TIPS may be considered as rescue management for refractory ascites secondary to portal hypertension, but caution in respect to the presence and/or development of peritoneal or other ectopic haematopoesis has to be taken.

Aged↗
PubMed2004

Hyperhaemolysis syndrome in a patient with myelofibrosis.

Hyperhaemolysis syndrome is well recognised in patients with sickle cell disease and beta-thalassaemia major, but has not been described in patients with other haematological diseases. We describe a case of fatal post-transfusion hyperhaemolysis occurring in a lady with myelofibrosis evolving into acute myeloid leukaemia. No free antibodies were identified in either pre- or post-transfusion serum samples. Since her haemoglobin (Hb) level after the reaction was very much lower, than of would have been the case if only the transfused red cells had haemolysed, it seems likely that this severe haemolytic transfusion reaction was an example of the so-called hyperhaemolysis syndrome.

Anemia↗
PubMed2002

Thalidomide in myelofibrosis with myeloid metaplasia: a pooled-analysis of individual patient data from five studies.

Trials to determine the effect of thalidomide in patients with Myelofibrosis with Myeloid Metaplasia (MMM) have produced inconclusive results due to different criteria for response and heterogeneous study participants. We undertook a pooled-analysis to assess the effects of such treatment on a larger series of cases and with a uniform assessment of response. We used updated data on 62 individual patients from 5 phase II trials that evaluated thalidomide therapy in MMM patients. Responsewas judged on individual disease parameters, on the improvement of the Dupriez risk categories and on the improvement of a 6 point "severity score" based on myeloproliferative and myelodepletive indexes of the disease. Overall, using standard dose of thalidomide, i.e. starting with no less than 100 mg/day, 49 patients (79%) had more than 4 weeks of therapy. Twenty-nine percent of patients with moderate to severe anemia showed an increase in hemoglobin or reduction/abolishment of blood transfusion requirements, 38% with moderate to severe thrombocytopenia had an increase in platelet counts, and 41% with high grade splenomegaly demonstrated a measurable reduction in splenic size. These effects led to an absolute decrease in the "severity" score in 44.9% of the patients. Major disease severity and high degrees of splenomegaly before therapy predicted response with a probability of 61.9%. However, worsening of the "severity" score was observed in 20.4% of the patients, 18% having a "myeloproliferative reaction" with leukocytosis and/or thrombocytosis. Sixty-six percent of the patients discontinued the drug before 6 months of treatment due to intolerance. In conclusion, there is a small but clear improvement of disease severity with thalidomide therapy in MMM. The potential for myeloproliferative reactions and the unfavorable dose-related toxicity profile argue for future studies using lower doses of this drug.

Adult↗